JPWO2012002189A1 - Method for producing valsartan - Google Patents

Abstract

According to the present invention, the valsartan enantiomer content is 0.20% or less, the crude valsartan having an organic solvent content of 3000 ppm to 25000 ppm is dried at a temperature of 50 to 65 ° C., and the enantiomer content of valsartan Is disclosed as a method for producing valsartan having an organic solvent content of 1000 ppm or less. The crude valsartan is obtained by, for example, precipitating valsartan obtained by synthesis in an organic solvent, and then separating the precipitated valsartan crystals, and the enantiomer content of valsartan is 0.20% or less, the organic solvent It is obtained by drying a wet body of valsartan having a content of 150000 ppm or more and 600000 ppm or less at a temperature of less than 50 ° C.

Description

  The present invention relates to a novel method for producing valsartan, which is useful as an angiotensin II receptor antagonist for the treatment of hypertension and the like.

  Valsartan is the official name, N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine, and has the following formula (1)

It is a compound shown by these. This valsartan is used as an angiotensin II receptor antagonist in antihypertensive drugs and the like.

This valsartan is used as a drug substance for the manufacture of antihypertensive drugs, so the purity must be very high. Conventionally, various production methods have been studied for the purpose of producing high-purity valsartan (see, for example, Patent Documents 1 to 7).
Valsartan is considered to be influenced by its chemical structure and crystallinity, but it is a compound that is very easy to occlude a solvent therein. Conventionally, a method for removing an organic solvent contained in valsartan (hereinafter also referred to as a drying method) has been studied.
Specifically, the following two methods are known as drying methods for reducing the organic solvent contained in valsartan to 5000 ppm or less.

  The first method is a method in which a solid crude valsartan produced by synthesis in an organic solvent is dried at room temperature, pulverized, and further dried (see Patent Document 1). More specifically, in this method, first, the crude valsartan is dried at room temperature until the content of the organic solvent is 5 to 20%, and then the dried crude valsartan is further pulverized to obtain 40 to 60 This is a method of drying at 0 ° C.

  As a second method, crude valsartan containing 10% or less of an organic solvent obtained through the synthesis step is (1) a method of pulverizing in water and then drying at 4 to 50 ° C., (2) 25 A method of drying in an atmosphere of ˜50 ° C. and a humidity of 30% or more, or (3) a method of drying at 5 to 60 ° C. for a long time is known (see Patent Document 2). More specifically, the second method is a method of drying valsartan containing a minimum amount of 2% organic solvent by any one of the methods (1) to (3). These methods are excellent drying methods, and can reduce the content of an optical isomer of valsartan, which is an impurity (hereinafter referred to as an enantiomer of valsartan), to 0.10% or less.

  The enantiomer of valsartan is represented by the following formula (2)

It is a compound shown by these.

  The above method is an excellent production method because the amount of the organic solvent can be reduced as compared with other known drying methods for drying valsartan in a temperature range of 20 to 60 ° C. However, according to the study by the present inventors, it has been found that it is difficult to reduce the organic solvent in valsartan to a high degree, specifically to less than 3000 ppm, even in the above method. In the case of the method described in Patent Document 2, there is a case where water treatment is required or humidity management is required, and there is room for improvement in that the operation becomes complicated.

International Publication No. 2006/058701 Pamphlet International Publication No. 2004/094391 Pamphlet European Patent No. 1849777 EP 1714963 Japanese Patent No. 2749458 Special table 2007-500733 gazette Special Table 2007-533727

  In the above conventional method, when the drying temperature of the crude valsartan is raised, the organic solvent content of the crude valsartan is naturally reduced. However, increasing the drying temperature increases the enantiomeric content of the impurities.

  Accordingly, an object of the present invention is to provide a method for producing valsartan having a low content of an organic solvent and a low content of an enantiomer as an impurity.

  The inventors of the present invention have made extensive studies to solve the above problems. The inventors of the present invention conducted various studies by paying attention to the relationship between the increased amount of enantiomer and the content of the organic solvent when valsartan was dried. As a result, when the content of the organic solvent in the valsartan was relatively high, it was found that the enantiomer content greatly increased when valsartan was dried at a relatively high temperature. Furthermore, when valsartan was dried at a relatively low temperature, it was found that there is a limit in reducing the content of the organic solvent.

  The drying method was further examined based on the above examination results. As a result, it was found that when a crude valsartan containing a predetermined amount or less of an organic solvent and a crude valsartan containing a predetermined amount or less of an enantiomer is dried at 50 to 65 ° C., the organic solvent can be efficiently reduced. . Furthermore, in this case, it has been found that an increase in enantiomers can be effectively suppressed, and as a result, highly pure valsartan can be obtained. The present invention has been completed on the basis of these results.

  The present invention is characterized by drying crude valsartan having a valsartan enantiomer content of 0.20% or less and an organic solvent content of 3000 ppm to 25000 ppm at a temperature of 50 to 65 ° C. Is 0.25% or less, and the organic solvent content is 1000 ppm or less.

  In the present invention, the crude valsartan is obtained by precipitating valsartan obtained by synthesis in an organic solvent, and then separating the precipitated valsartan crystals, so that the enantiomer content of valsartan is 0. It is preferably obtained by drying a valsartan wet body having an organic solvent content of 150,000 to 600,000 ppm at a temperature of less than 50 ° C.

  By using the crude valsartan obtained by the above method, valsartan having high purity can be obtained efficiently.

  According to the present invention, valsartan having a valsartan enantiomer content of 0.25% or less and an organic solvent content of 1000 ppm or less can be produced.

  According to the present invention, the organic solvent content of valsartan can be reduced to an extremely small amount as compared with the conventional production method. As a result, dried and highly purified valsartan can be obtained with high yield and high efficiency. Valsartan is used as an angiotensin II receptor antagonist in antihypertensive drugs and the like. Valsartan obtained by the above production method can be used as the active ingredient in a highly reliable preparation without any change in crystal form or dissolution behavior.

  Furthermore, highly pure valsartan can be produced without increasing the enantiomer of valsartan, which is an impurity. Therefore, its industrial utility value is extremely high.

FIG. 1 is a graph showing the amount of increase in enantiomers when crude valsartan having different organic solvent contents is dried at 60 ° C.

  The present invention relates to a method for producing valsartan and high-purity valsartan. The present invention provides a high-purity valsartan by preparing a crude valsartan having a predetermined range of enantiomer content and a predetermined range of organic solvent content, and drying the crude valsartan in a temperature range of a predetermined range. Features.

  In the present invention, drying refers to an operation of reducing the amount of organic solvent contained in the crude valsartan to be dried.

In the present invention, the organic solvent content refers to the mass ratio of the organic solvent contained in valsartan to be measured. The organic solvent content is a value measured by a method by gas chromatography (GC) described in Examples described later.
The enantiomer content was measured by high performance liquid chromatography (HPLC) described in Examples. In the obtained chromatogram, the ratio (area%) of the peak area of the enantiomer to the total peak area of valsartan and the enantiomer was defined as the enantiomer content.

  Valsartan purity was measured by HPLC as described in the examples. In the obtained chromatogram, the ratio (area%) of the total peak area of valsartan and the enantiomer of valsartan to the total peak area of the measurement sample was defined as the purity of valsartan.

  Hereinafter, this manufacturing method will be described step by step. First, crude valsartan to be dried will be described.

(Coarse Valsartan)
In the production method of the present invention, the starting material is crude valsartan. The crude valsartan has an organic solvent content of 3000 ppm to 25000 ppm and an enantiomer content of 0.20% or less.

  In the production method of the present invention, the crude valsartan is dried at a temperature of 50 to 65 ° C. to obtain valsartan having an enantiomer content of valsartan of 0.25% or less and an organic solvent content of 1000 ppm or less.

  The crude valsartan used in the production method of the present invention is not particularly limited as long as it satisfies the organic solvent content and the enantiomer content, and any crude valsartan can be used.

  In addition, since this crude valsartan is a thing close | similar to a final product, it is preferable that it is a high purity thing. The purity of the crude valsartan cannot be limited unconditionally due to a slight difference depending on production conditions and the like, but is preferably 99.50% or more. Considering industrial production and use of valsartan after drying as the drug substance, it is preferably 99.90% or more.

(Organic solvent contained in crude valsartan)
The organic solvent contained in the crude valsartan is derived from an organic solvent used for synthesis of valsartan, an organic solvent used during purification, and the like. As a solvent used for synthesis and purification, there are usually the following organic solvents.

  Alcohols such as methanol, ethanol, propanol, isopropyl alcohol, 1-butanol, 2-butanol, pentanol, hexanol, octanol, dimethyl ether, diethyl ether, ethyl methyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, tetrahydropyran, dioxane, etc. Ethers, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, isovaleronitrile, acrylonitrile and other nitriles, hexane, heptane, pentane, octane, cyclohexane, cycloheptane, methylcyclohexane, methylcycloheptane, Aliphatic hydrocarbons such as cyclooctane and decalin, acetone, methyl ethyl ketone, 3-methyl-2-butyl Non, pentanone, cyclopentanone, ketones such as cyclohexanone, aromatic hydrocarbons such as toluene, xylene, and ethylsenzen, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, and halogenations such as dichloromethane and dichloroethane chloroform Aliphatic hydrocarbons, acetates such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, t-butyl acetate, amides such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone Etc. The solvent contained in these valsartan may be one type or plural cases.

  Among these solvents, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, and 1-butanol, ethers such as dimethyl ether, diethyl ether, ethyl methyl ether, diisopropyl ether, and tetrahydrofuran, nitriles such as acetonitrile, and hexane , Aliphatic hydrocarbons such as heptane, pentane, octane, cyclohexane and methylcyclohexane, ketones such as acetone, methyl ethyl ketone and 3-methyl-2-butanone, aromatic hydrocarbons such as toluene and xylene, chlorobenzene and dichlorobenzene Halogenated aromatic hydrocarbons such as, halogenated aliphatic hydrocarbons such as dichloromethane and chloroform, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, etc. Acetic acid esters, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, in the case of using the N- methylpyrrolidinone amides Don such as synthesis and purification of valsartan, because it is easy to reduce the content of the solvent in the crude Valsartan obtained, preferably.

  Furthermore, among these solvents, the organic solvent is preferably an acetate ester, an aliphatic hydrocarbon, or a mixed solvent thereof in that the preparation of crude valsartan is facilitated. These organic solvents are organic solvents that can be suitably used when purifying valsartan synthesized by a known method. When these organic solvents are used as a solvent for recrystallization of valsartan, the enantiomer content of crude valsartan can be effectively reduced.

  Acetic esters are used as good solvents for valsartan. Aliphatic hydrocarbons are used as poor solvents for valsartan. Considering the crystallinity of the finally obtained valsartan, the reduction of the enantiomer content, and the reduction of the organic solvent content, among these solvents, acetates are preferable, and ethyl acetate is most preferable.

  In the production method of the present invention, crude valsartan having an organic solvent content of 3000 ppm to 25000 ppm is dried at 50 to 65 ° C. When crude valsartan having an organic solvent content exceeding 25000 ppm is dried at a temperature within the above temperature range, the content of the enantiomer increases, which is not preferable.

  Although the cause of this is not clear, the present inventors presume as follows. That is, when Valsartan contains an organic solvent exceeding 25000 ppm, Valsartan is easily dissolved in the organic solvent during drying at a temperature within the above temperature range. As a result, valsartan becomes amorphous and is converted to an enantiomer. According to the above concept, it can be seen that the drying within the above temperature range and the limitation of the organic solvent content of the crude valsartan before drying have very important meanings.

  In order to better suppress the increase in enantiomer content, the amount of the organic solvent contained in the crude valsartan is preferably 20000 ppm or less, and particularly preferably 15000 ppm or less. The lower limit of the amount of organic solvent contained in the crude valsartan is preferably as small as possible. However, in consideration of restrictions on production facilities, economy, etc., the lower limit of the amount of organic solvent contained in the crude valsartan is practically 3000 ppm or more, preferably 4000 ppm or more, and more preferably 5000 ppm or more.

  The organic solvent content contained in the crude valsartan is the content of a single organic solvent when the solvent is a single organic solvent. When a plurality of solvents are included, it is the total content of the plurality of organic solvents.

(Enantiomer contained in crude valsartan)
Enantiomers contained in crude valsartan are impurities. It is desirable that the enantiomer content of the final product valsartan, such as the drug substance, be as low as possible. In order to meet this demand, the enantiomer content of the crude valsartan used in the present invention is 0.20% or less, preferably 0.15% or less, more preferably 0.10% or less, and 0.05% or less. Particularly preferred.

  The lower limit of the enantiomer content of the crude valsartan is ideally 0.00% (below the detection limit). However, considering the industrial production of valsartan, the enantiomer content of crude valsartan is preferably 0.01% or more, and more preferably 0.02% or more.

  Enantiomers in crude valsartan are produced when synthesizing valsartan. This enantiomer can be efficiently reduced by, for example, a purification method in which crystallization is performed using acetic esters which are good solvents.

  In order to prepare the crude valsartan having the above enantiomeric content for use in the present invention, after synthesis of valsartan by a known method, an organic compound mainly composed of acetate esters, particularly ethyl acetate (or ethyl acetate alone may be used) It may be purified by crystallizing valsartan in a solvent. Crystallization can be repeated multiple times until the valsartan is of the required purity. This crystallization can reduce enantiomers in valsartan. Crystallization includes purification methods such as recrystallization and crystallization.

  Next, a preferred method for preparing crude valsartan will be described.

(Preferred method for preparing crude valsartan)
In the production method of the present invention, first, crude valsartan is prepared. There is no restriction | limiting in particular as a preparation method of crude valsartan, For example, there exist the method of synthesize | combining by a well-known method, and the method of purchasing a commercial item and refine | purifying as needed.

  Hereinafter, a method for preparing valsartan by a known method and preparing crude valsartan which is a starting material of the present invention will be described.

  In this method of preparing crude valsartan, first, valsartan is synthesized according to the method described in the above-mentioned patent document to obtain a wet body of valsartan. Next, the organic solvent content and enantiomer content of the wet body of valsartan are adjusted so as to be within the ranges defined in the present invention. Hereinafter, a method for preparing crude valsartan will be described with a specific example.

[Manufacture of wet bodies]
When referring to the method described in Patent Document 6, valsartan is synthesized as follows. First, valsartan is synthesize | combined through the various manufacturing processes described in patent document 6, and valsartan is isolate | separated from the reaction mixture obtained by a conventional method. The obtained valsartan is a solid containing a large amount of an organic solvent used in the reaction.

  Next, the separated valsartan is crystallized using an organic solvent such as ethyl acetate. The obtained valsartan crystal is a solid wet substance containing an organic solvent used for crystallization. The content of the organic solvent occluded in the wet body of valsartan exceeds 25000 ppm.

  In addition, the further detailed specific example about the said crystallization is described below. In this example, first, the separated valsartan is dissolved in ethyl acetate at 50 ° C. Subsequently, valsartan precipitates by cooling to 10 degreeC. Solid-liquid separation is performed to obtain a wet body of valsartan containing ethyl acetate.

  As another specific example, valsartan with few enantiomers is synthesized by the method described in Patent Document 2, and the valsartan is recrystallized in the same manner as described above to obtain a wet body.

  The content of the enantiomer of the wet body of valsartan (hereinafter sometimes simply referred to as “wet body”) is preferably 0.20% or less. In order to further increase the purity of the purified valsartan finally obtained, the content of the enantiomer contained in the wet body is more preferably 0.15% or less, further preferably 0.10% or less, 0.05 % Or less is particularly preferable.

  As a method of bringing the content of the enantiomer of the wet valsartan into the above range, a method of purification by crystallization in an organic solvent is preferable. By repeating the crystallization, the enantiomer content can be controlled within the above range. The organic solvent used for crystallization is preferably an acetate ester, particularly ethyl acetate.

  The lower limit of the enantiomeric content of the wet body is preferably the same as the lower limit of the enantiomeric content of the crude valsartan, specifically 0.00% (below the detection limit). . However, considering the case of industrial production, it is desirable that it is 0.01% or more, and further it is desirable that it is 0.02% or more.

  The purity of valsartan in the wet body is preferably in the same range as the purity of the crude valsartan. Specifically, the purity is preferably 99.50% or more, and more preferably 99.90% or more in consideration of industrial production.

  As described above, the wet body is a solid obtained by crystallizing valsartan in an organic solvent and solid-liquid separation. Therefore, the organic solvent content of the wet body is usually 150,000 ppm or more and 600000 ppm or less. However, the content of the organic solvent becomes 150,000 ppm or more and 500,000 ppm or less if dried or left a little.

[Drying wet body]
By drying the wet body having an enantiomer content of 0.20% or less, an organic solvent content of 150,000 ppm to 600000 ppm, and a purity of 99.50% or more, the amount of the organic solvent is reduced and the present invention is reduced. To obtain crude valsartan for use in During drying, the increase in enantiomer is minimized.

  It is preferable to induce the wet body to crude valsartan having an organic solvent content of 25000 ppm or less as soon as possible. In the most preferred embodiment, the wet body obtained by precipitating synthesized valsartan crystals from an organic solvent and separating the organic solvent and the crystals is dried without storage and the organic solvent content is 25000 ppm or less. It is preferable to lead to crude valsartan.

  The reason why this method is preferable is not clear. However, the present inventors consider as follows. That is, after obtaining the wet body, without drying the wet body, by continuously drying and leading to crude valsartan, it is possible to suppress dissolution of the crystal surface of valsartan by the remaining solvent, It can prevent becoming a lump. As a result, crude valsartan with a reduced organic solvent content can be produced.

  According to the study by the present inventors, it was found that enantiomers tend to increase when valsartan is handled at a high temperature. In particular, when the amount of the organic solvent remaining in valsartan is large, the tendency is remarkably increased.

  FIG. 1 is a graph showing the relationship between the organic solvent content in the crude valsartan and the increase in enantiomer when the crude valsartan having different organic solvent contents is dried at 60 ° C. From FIG. 1, it can be seen that when the organic solvent content in the crude valsartan exceeds 25000 ppm, the amount of increase in enantiomer increases rapidly.

  Considering the data of the graph, it can be seen that it is preferable to dry at a temperature as low as possible in order to obtain the crude valsartan by drying the wet body containing usually 150,000 ppm or more of the organic solvent. According to the study by the present inventors, by drying at a temperature of less than 50 ° C., the crude valsartan can be obtained by reducing the organic solvent without increasing the enantiomer.

  In order to further reduce the increase in enantiomer, the drying temperature is preferably 45 ° C. or lower. The lower limit of the drying temperature is not particularly limited, but is preferably 0 ° C. or higher, more preferably 10 ° C. or higher. In order to reduce the organic solvent in a short time, the drying temperature is preferably 35 ° C. or higher. In addition, the said drying temperature is the temperature of the atmosphere at the time of drying a wet body.

  In order to efficiently reduce the organic solvent from the wet body within the above temperature range, the organic solvent used for the precipitation of crystals is preferably an acetate ester, particularly ethyl acetate.

  When the wet body is dried in the above temperature range, the atmosphere is not particularly limited, but is preferably performed in air or an inert atmosphere, particularly preferably in a nitrogen atmosphere or under reduced pressure. . In particular, drying is preferably performed under reduced pressure in order to shorten the period in which the wet body exists and at the same time increase productivity. When drying under reduced pressure, the drying time is 3 to 100 hours, preferably 8 to 50 hours. The degree of vacuum may be appropriately determined according to the structure of the apparatus to be dried, the amount of organic solvent contained in the wet body, the drying time (treatment time), and the like, and is usually preferably 0.01 to 100 mmHg.

  Known dryers can be used as dryers to obtain crude valsartan by drying the wet body in the above temperature range under reduced pressure. For example, a conical dryer or a shelf dryer is preferable, and the wet body can be efficiently dried by using this.

  By operating according to the above method, it is possible to efficiently obtain a crude valsartan having an enantiomer content of valsartan of 0.20% or less and an organic solvent content of 3000 ppm to 25000 ppm as impurities. In this case, the purity of the crude valsartan is preferably 99.50% or more as described above.

  The greatest feature of the present invention is that the crude valsartan is dried at a temperature of 50 to 65 ° C. Next, a method for drying this crude valsartan will be described.

(Drying method of crude valsartan)
In the present invention, crude valsartan having an enantiomer content of 0.20% or less and an organic solvent content of 3000 ppm to 25000 ppm is dried within a temperature range of 50 to 65 ° C. By using crude valsartan having an enantiomer content of 0.20% or less, the content of enantiomer contained in the finally obtained valsartan (hereinafter sometimes referred to as purified valsartan) can be reduced.

  Furthermore, since crude valsartan having an organic solvent content of 3000 ppm or more and 25000 ppm or less is used and dried at a temperature within a temperature range of 50 to 65 ° C., the organic solvent of crude valsartan is suppressed in a short time while suppressing the increase in enantiomers. The content can be reduced. As described above, when the crude valsartan having an organic solvent content exceeding 25000 ppm is used, an increase in the enantiomer content of the purified valsartan cannot be suppressed even if it is dried at a temperature of 50 to 65 ° C.

  When the crude valsartan is dried at a temperature lower than 50 ° C., the organic solvent cannot be sufficiently reduced, which is not preferable. On the other hand, when the crude valsartan is dried at a temperature exceeding 65 ° C., even if the organic solvent content of the crude valsartan is 25000 ppm or less, the enantiomer content of the purified valsartan is not preferable.

  In order to efficiently reduce the organic solvent content and enantiomer content of the purified valsartan, the drying temperature of the crude valsartan is more preferably 55 to 65 ° C, further preferably 55 to 60 ° C. This drying temperature is the temperature of the atmosphere when the crude valsartan is dried.

  When the crude valsartan is dried in the above temperature range, the atmosphere is not particularly limited, but is preferably under a nitrogen atmosphere and under reduced pressure. When it is necessary to dry the crude valsartan in a short time, it is preferable to dry under reduced pressure. When drying under reduced pressure, the degree of reduced pressure is appropriately determined according to the structure of the apparatus to be dried, the amount of organic solvent contained in the wet body, the drying time, and the like.

  Usually, the degree of vacuum is preferably 0.01 to 100 mmHg. In addition, when drying under this reduced pressure, the drying time may be appropriately determined according to the organic solvent content of the desired purified valsartan, but is usually 3 to 100 hours, preferably 3 to 50 hours. is there.

  As a dryer used for drying crude valsartan in the above temperature range under reduced pressure, a known dryer may be mentioned. For example, a conical dryer or a shelf dryer is preferable. By using this, the crude valsartan can be efficiently dried.

(Dried Valsartan)
The organic solvent content of the purified valsartan obtained by drying as described above is usually 1000 ppm or less, preferably 500 ppm or less. The lower limit of the organic solvent content of purified valsartan is most preferably 0 ppm (below the detection limit). However, in industrial valsartan production, the organic solvent content is usually 20 ppm or more.

  The enantiomer content of purified valsartan is 0.25% or less, preferably 0.20% or less, and particularly preferably 0.10% or less. The lower limit of the enantiomer content of purified valsartan is most preferably 0.00% (below the detection limit). However, in industrial production of valsartan, the enantiomer content is usually 0.01% or more.

  The purity of the purified valsartan depends on the purity of the crude valsartan used, and cannot be defined unconditionally. However, according to the production method of the present invention, the purity of the purified valsartan is 99.50% or more, preferably 99.90% or more.

  As described above, the purified valsartan obtained by the production method of the present invention has a low organic solvent content, a very low enantiomeric content, and a high purity. The purified valsartan can be pulverized as necessary, and can be suitably used as an angiotensin II receptor antagonist as a therapeutic agent for hypertension and the like.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited at all by these Examples.

(Measurement of organic solvent content)
The organic solvent content was measured by gas chromatography (GC). The organic solvent content was quantified using a calibration curve prepared in advance. The content was expressed in ppm (mass basis).
The equipment used and the measurement conditions are described below.
Equipment: Agilent 6890N
Detector: Flame ionization detector column: Capillary column in which the inner surface of a fused silica tube having an inner diameter of 0.53 mm and a length of 30 m is coated with polyethylene glycol for gas chromatography at a thickness of 3 μm.
Column temperature: 35 ° C. for 6 minutes after injection, then heated to 90 ° C. at 30 ° C. per minute and maintained at 90 ° C. for 3 minutes. Further, the temperature was raised to 230 ° C. at 35 ° C. per minute and maintained for another 3 minutes.
Column pressure: 8.5 psi at 3 psi after injection, then pressure increased to 6 psi at 1 psi per minute and maintained at 6 psi for 8.5 minutes.
The measurement conditions were inlet temperature (200 ° C.), detector temperature (250 ° C.), carrier gas (helium), and split (1/10).

  In addition, the said measurement melt | dissolves the target valsartan in a solvent, and implements it. The solvent used for dissolving valsartan may be any solvent that can be separated from the organic solvent to be detected under the above measurement conditions. In this measurement, dimethylformamide was used as a solvent for dissolving valsartan.

(Measurement of valsartan purity)
Valsartan purity was measured using high performance liquid chromatography (HPLC). The apparatus and measurement conditions are described below.
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 225 nm
Column: Stainless steel tube column with an inner diameter of 4.6 mm and a length of 15 cm. The filler was 5 μm octadecylsilylated silica gel for liquid chromatography.
Mobile phase: A mixed solution of 500 mL of acetonitrile, 500 mL of water and 1 mL of acetic acid.
The measurement conditions were mobile phase flow rate (1 mL / min) and column temperature (constant temperature around 35 ° C.).

(Measurement of enantiomer content)
The enantiomer content was measured by high performance liquid chromatography (HPLC). The apparatus and measurement conditions are described below.
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 230 nm
Column: Stainless steel tube column with an inner diameter of 4.6 mm and a length of 25 cm. The filler was silica gel for liquid chromatography coated with 5 μm cellulose carbamate derivative.
Mobile phase: 850 mL of hexane, 150 mL of 2-propanol and 1 mL of trifluoroacetic acid.
The measurement conditions were mobile phase flow rate (0.8 mL / min) and column temperature (constant temperature around 35 ° C.).

Production Example 1
(Manufacture of valsartan wet body)
According to Patent Document 6, valsartan was synthesized and its wet body was produced.
In a flask equipped with a reflux condenser, 1400 mL of methanol was placed, and N-{[2 ′-(1-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl} -N-valeryl-L-valine benzyl. 660 g of ester was added. The flask was heated to dissolve the ester under methanol reflux. Further, the ester was refluxed for 8 hours to detritylate the ester. Next, 75 g of Pd—C catalyst (3%, containing 50% water) was added to the flask. By performing a reduction reaction at 40 ° C. for 16 hours under a hydrogen atmosphere (0.1 MPa), the ester was debenzylated to synthesize valsartan.

After confirming that the reaction had progressed by thin layer chromatography (hereinafter also referred to as TLC), the reaction solution was filtered to remove the Pd-C catalyst, and the filtrate was concentrated.
To the residue obtained by concentrating the filtrate, 200 mL of isopropyl alcohol and 800 mL of ion exchange water were added, and then the pH was adjusted to 8 with 1350 mL of a 10% by mass aqueous potassium hydroxide solution. Each time, extraction operation was performed twice using 750 mL of toluene. Thereafter, 1250 mL of ethyl acetate was added to the aqueous layer, and the pH was adjusted to 1 using 200 mL of concentrated hydrochloric acid.

  After separating the organic layer, 600 mL of ethyl acetate was added to the aqueous layer and back-extracted. The organic layers composed of ethyl acetate were combined and washed twice with 250 mL of ion exchange water. The organic layer washed with water was concentrated under reduced pressure at 50 ° C. to obtain a concentrate (mainly valsartan).

  Subsequently, 1200 mL of ethyl acetate was added to the concentrate, and the concentrate was dissolved at 50 ° C. After cooling to 10 ° C., the mixture was aged for 1 hour. The precipitated crystals were separated into solid and liquid. The obtained crystals were recrystallized twice with ethyl acetate to obtain 150 g (28% yield) of Valsartan wet. The recrystallization method was the same as the method for removing the crystals from the concentrate.

  The obtained wet body of valsartan was analyzed by HPLC. Valsartan had a purity of 99.96% and an enantiomer content of 0.03%. The organic solvent content was confirmed by GC. The content of ethyl acetate was 510350 ppm.

Example 1
(Preparation of crude valsartan)
40 g of the valsartan wet body obtained in Production Example 1 was placed in a glass petri dish having an inner diameter of 20 cm, and dried under reduced pressure (10 mmHg) at 40 ° C. for 10 hours with a shelf dryer to prepare crude valsartan. When the purity of crude valsartan was measured by HPLC analysis, valsartan 99.96%, enantiomeric content 0.03%, and organic solvent content analyzed by GC were ethyl acetate content 10410 ppm.

(Drying crude valsartan)
The crude valsartan was dried with a shelf dryer under reduced pressure (10 mmHg) at 60 ° C. for 10 hours to obtain crude valsartan. When the purity was measured by HPLC analysis, valsartan 99.96%, enantiomer 0.04%, and the amount of organic solvent analyzed by GC was ethyl acetate content 178 ppm.

Examples 2-7
Purified valsartan was produced in the same manner as in Example 1 except that the drying temperature and time for preparing the crude valsartan of Example 1 and the drying temperature and time for drying the crude valsartan were changed. The results are shown in Table 1.

Comparative Examples 1-6
Valsartan was produced in the same manner as in Example 1 except that the drying temperature and time for preparing the crude valsartan of Example 1 and the drying temperature and time for drying the crude valsartan were changed. The results are shown in Table 2.

Of the above Examples and Comparative Examples, the case where the drying temperature of the crude valsartan was 60 ° C. was taken out, and the relationship between the amount of the organic solvent contained in the crude valsartan and the increased amount of enantiomer after drying is shown in FIG. In Comparative Examples 3 to 5 in which the crude valsartan having an organic solvent content of more than 25000 ppm was dried, the enantiomers were clearly increased in comparison with Examples 4 to 8 in which the crude valsartan having an organic solvent content of 25000 ppm or less was dried under the same drying conditions. The amount was large.

Claims (7)

The enantiomer content of valsartan is 0.25% or less, the crude valsartan having an organic solvent content of 3000 ppm to 25000 ppm is dried at a temperature of 50 to 65 ° C., and the enantiomer content of valsartan is 0.25 %, And a method for producing valsartan having an organic solvent content of 1000 ppm or less. The crude valsartan is obtained by precipitating valsartan obtained by synthesis in an organic solvent, and then separating the precipitated valsartan crystals. The enantiomer content of valsartan is 0.20% or less, and the organic solvent is contained. The method for producing valsartan according to claim 1, which is obtained by drying a wet body of valsartan having an amount of 150,000 ppm to 600000 ppm at a temperature of less than 50 ° C. The method for producing valsartan according to claim 1 or 2, wherein the organic solvent is an acetate ester. The method for producing valsartan according to claim 1 or 2, wherein the drying is performed in a nitrogen atmosphere under reduced pressure. The method for producing valsartan according to claim 1 or 2, wherein the purity of the crude valsartan is 99.50% or more. Valsartan having an enantiomer content of valsartan of 0.25% or less and an organic solvent content of 1000 ppm or less. The valsartan according to claim 6, wherein the purity of valsartan is 99.50% or more.

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